Microbiota, small intestine inflammation and type 2 diabetes

Li Wen, MD, PhDYale University School of Medicine

? Viruses? Toxins

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ENVIRONMENT

GENETIC PREDISPOSITION

PATHOGENESIS OF TYPE 2 DIABETES

DIABETES

Diet and life style

Gut bacteria

CDC 2014

White Adults Black Adults

Hispanic Adults

Genetic influences on human T2D

Genetic influences on Mouse Models

Leptin deficiency TLR5 deficiency

Outline• What are gut microbiota?• How is the composition determined?• What have animal models taught us?• Is the gut microbiome influenced by DIET and

linked to human type 2 diabetes?• Is there a gut signature that promotes

intestinal inflammation and subsequently low grade systemic inflammation in human type 2 diabetes?

Gut Microbiota (Gut Flora)

Which bacteria make up the gut microbiota?

There are 4 large groups (phyla)

Actino-bacteria

Bacteroidetes

Firmicutes

ProteobacteriaThe genes of the bacteria in our gut are 150 times larger than that in the human genome (Qin et al, 2010). The mass of the bacteria may reach up to 1.5 Kg.

What factors determine our gut bacterial composition?

Birth –Mode of delivery

Infant feeding methods

Infections

Antibiotics

Diet

“Hygiene”

During the development

Environmental influences on human T2D

Diet High fatHigh calorie“Junk food”

Drugs: Wide usage of antibiotics

Life style: physical inactivity

Effect of Diet on Obesity

10% fat 35% fat 60% fat

Enterotype of Human Gut Microbiota

Wu, et al, Science 2011

Animal protein enriched diet

Carbohydrate enriched diet

Effect of Diet on Human Gut Microbiota

David, et al; Nature, 2014

Major findings from metagenome-wide association studies (MGWAS) in patients with T2D

Butyrate-producing Roseburia intestinalis and Faeclibacterium prausnitzii concentrations are lower in T2D

Lactobacillus gasseri and Streptococcus mutans and certain Clostridiales are higher in T2D

Genes involved in vitamin synthesis is lower in T2D

Proteobacteria are higher in T2D

Increased expression of microbiotal genes involved in oxidative stress, that is, overall a pro-inflammatory signature in the intestinal microbiota

Shortcomings of the studies: heterogenous populations, data on diabetes medication incomplete and its role unclear, studies lack gender balance; mucosa-associated microbiota not studied Qin, et al. Nature, 2012

Karlsson, et al. Nature, 2013Tilg, Gut, 2014

Evidence for a beneficial effect of Akkermansia muciniphila on metabolic functions

A Mucin-degrading Gram-negative bacterium constituting 3-5% of the intestinal microbiota

Concentrations inversely correlated with obesity and T2D in many experimental and human studies

Prebiotic consumption such as oligofructose is metabolically beneficial and increases A muciniphila concentrations

Administration of A muciniphila to mice improves weight loss, metabolic control and adipose tissue inflammation

Metformin (T2D drug) increases A muciniphila concentrations

Controversies: some animal/human studies show conflicting results

H Tilg et al, Gut 2014

Gut Microbiota and Metabolism in Yogurt Consumers vs non Yogurt Consumers

Group N(n=21)

Group Y(n=30)

P value

b-galactosidase 68.9+/-2.43 85.43+/-5.1 0.048

Bacterial enzyme activities

Group N(n=21)

Group Y(n=30)

P value

Lactobacillus bulgaricus

28% 68% 0.003

Bacterial Composition

Alvaro et al. BJN, 2007

“You Are What You Eat”

Gastric bypass – the most effective intervention of obesity and T2D

Alpha diversity

Diversity of Fecal Microbiota Is Significantly Increased After Gastric Bypass

Am J Clin Nutr. 2013 Jul;98(1):16-24

Summary• What are gut microbiota?

a complex community of bacteria in the intestine (endogenous non-self)• How is the composition determined initially?

Birth route, feeding, medication, sanitation• What have animal models taught us?

Genetic, diet and environmental factors can alter gut microbiota• Is the gut microbiome influenced by DIET and linked to human

type 2 diabetes?YES

• Is there a gut signature that promotes intestinal inflammation and subsequently low grade systemic inflammation in human type 2 diabetes?

Most likely (mouse models, human studies, gastric bypass study)• Can surgery treat T2D and by what mechanism?

Gastric bypass can effectively treat obesity and T2D. Change diet and gut microbiota.

Acknowledgements

Funded by NIH and ADA

Collaborators

Andrew Duffy (Yale)Robert Sherwin (Yale)Susan Wong(Cardiff, UK)